Enantioselective de novo construction of 3‑oxindoles via organocatalyzed formal [3 + 2] annulation from simple arylamines

The de novo construction of enantioenriched 3-hydroxyindolenines and 3-oxindoles from easily available starting materials has been highly desired. Herein, an enantioselectively intermolecular direct [3 + 2] annulation of aryl amine with 2,3-diketoesters to construct 3-hydroxyindolenines with a chiral tertiary alcohol has been disclosed. The results of control experiments and DFT calculation revealed that π − π interaction plays a pivotal role in the enantioselectivity-determining process of [3 + 2] annulation. The following unusual concerted [1,2]-ester migration provides a family of chiral 3-oxindoles in good to excellent yields with excellent enantioselectivity.

Reviewer #1: Remarks to the Author: This manuscript by Cui and co-workers described a protocol for the de novo construction of chiral 3oxindoles bearing a quaternary chiral center using arylamines and diketoesters as starting materials.CPAs were used to promote the asymmetric othro Friedel-Crafts alkylation of arylamine to give 3hydroxyindolenines, which underwent [1,2]-ester migration to afford 3-oxindoles with excellent stereocontol.Even though the reported chemistry disclosed a new method for the synthesis of these chiral indole derivatives, the research is too specialized for publication in Nat.Commun., and some issues need be addressed: 1) The scope of substrate in this study is too narrow.Only 1-naphthylamine and its analogues, such as 4-aminoindole, are applicable, 2-naphthylamine and aniline derivatives were not examined.In addition, only primary arylamines were used, what is the result of N-alkyl arylamines?Those results should be included in the manuscript.2) The [1,2]-ester migration is interesting, however, the mechanism and driving force of this process was not studied.The absolute configuration of 3-hydroxyindolenine intermediate should also be given to elucidate the stereochemistry in this process.3)In the SI, P95-96, the HPLC spectra indicated that there are two diastereoisomers for compound 4dq with a dr value of 1:1.Are there two stereogenic centers?This result should be discussed in the manuscript.
Reviewer #2: Remarks to the Author: In the manuscript, Cui and co-workers reported the organocatalyzed construction of chiral 3-oxindoles from primary 1-naphthyl-type amine and 2,3-diketoesters, through a sequential enantioselective ortho-FC reaction, condensation and 1,2-ester migration.A series of chiral 3-oxinodles bearing a tetrasubstituted stereogenic center was achieved in good yields and enantioselectivities.It is challenging to realize the intermolecular ortho-FC reaction of primary aryl amines and ketones, due to the side condensation reaction and para-selectivity.Some interesting results were presented in the manuscript, and the direct construction of the related scaffolds, which may have potential applications, is challenging.This reviewer thinks that the current work might contain the novel findings meriting the publication on Nat.Commun., however, a number of issues might be addressed before decision is made, especially for the mechanism study.1) In general, this manuscript was not well prepared.For example, the data in Table 1 were not clearly elucidated.According the formula in Table 1, two steps were required to give the final product 4aa, but the authors did not mentioned it in the text.In addition, TsOH was used for some entries, and no explanation was provided too.The authors should check the whole manuscript, guaranteeing it is written in a clearly understandable pattern.
2) The final enantioselective 1,2-ester migration process is intriguing; nevertheless, the suggested direct migration of ester group to electrophilic ketimine group might not be reasonable.Since TsOH was used for the ester migration reaction at rt in one-pot, did the chiral PA also play a role in this process?More control experiments might be conducted with the isolated chiral 3aq (Fig. 3): Will the ee value of chiral 3aq be changed when sole TsOH is used?Moreover, the authors are strongly encouraged to conduct some DFT calculations to illuminate the reaction pathway and the stereocontrol modes.
3) Will the transformation of imine product 7 be promoted by a chiral PA? 4) In general, the scope for both partners were relatively limited.How about 2-naphthylamine or even aniline-type ones?How about secondary amine substrates?Are the alkyl-substituted diketoesters applicable? 5) Significant ee losses were observed in the transformation of 4ag to 8. Why?
Comments: This manuscript by Cui and coworkers presents the use of a chiral phosphoric acid as catalyst for the enantioselective synthesis of chiral 3-oxindoles via ortho-Friedel-Crafts addition and novel [1,2]-ester migration.In particular, the [1,2]-ester migration reported in this paper is rarely seen in reactions.However, firstly, the chemistry presented in this communication is far from being very effective in terms of synthetic application.Meanwhile, the reaction time is too long.In terms of substrate, there are only polycyclic compounds, and there is no benzene as a substrate for reaction.On one hand, When the 2,3-diketoesters is a 2-substituted aromatic ring, the enantioselectivity is only 22% e.e.. On the other, the total number of substrates was insufficient to support publication in nature communication.Secondly, the title was chiral 3-oxindoles enantioselective synthesis.However, no direct synthesis of related compounds was found in this paper, basically all naphthalene indole compounds.Thirdly, there is insufficient evidence in mechanism research to demonstrate the formation process of chirality.Finally, the further transformation of the product is too simplistic.For all these reasons, I cannot recommend publication of this work in nature communication.Other issues: 1) Why does the reaction catalyzed with CPA could selectively afford the desired product and the reaction catalyzed with diphenyl phosphate give the imine intermediate.
2) The reaction proceeds two-steps one pot to afford the final products.Why not stop in the first step to obtain the chiral imine product, which could further reduce to the chiral amine product?In this way, sufficient data could be obtained.

Other minor issues
The NMR spectrum should correspond to the serial number of each compound.For compounds containing fluorine, their carbon spectrum splitting should be amplified.The HPLC peak of compound 4jq is too low.

To the comments of Reviewer 1
This manuscript by Cui and co-workers described a protocol for the de novo construction of chiral 3-oxindoles bearing a quaternary chiral center using arylamines and diketoesters as starting materials.CPAs were used to promote the asymmetric otho Friedel-Crafts alkylation of arylamine to give 3-hydroxyindolenines, which underwent [1,2]-ester migration to afford 3oxindoles with excellent stereocontol.Even though the reported chemistry disclosed a new method for the synthesis of these chiral indole derivatives, the research is too specialized for publication in Nat.Commun., and some issues need be addressed: Responses: The introduction of the manuscript was modified.The de novo construction of chiral 3-oxindoles would be interesting to interdisciplinary readership of Nature Communications.
1) The scope of substrate in this study is too narrow.Only 1-naphthylamine and its analogues, such as 4-aminoindole, are applicable, 2-naphthylamine and aniline derivatives were not examined.In addition, only primary arylamines were used, what is the result of N-alkyl arylamines?Those results should be included in the manuscript.

Responses:
The N-alkyl arylamines as the substrates were examined.The results were added in the manuscript (page 8-9) and Table 3.
2) The [1,2]-ester migration is interesting, however, the mechanism and driving force of this process was not studied.The absolute configuration of 3-hydroxyindolenine intermediate should also be given to elucidate the stereochemistry in this process.

Responses:
The absolute configuration of 3-hydroxyindolenine was identified in the Fig. 2.And the exclusive enantioselective [1,2]-ester migration was also demonstrated by the control experiments."To validate if the 3-hydroxyindolenine 3 was a key intermediate, the control experiment of 1a and 2q using (S)-6b as the catalyst was conducted (Fig. 2a).3aq was obtained in 99% yield with 98% ee.This result implied that this methodology could also be used for catalytic enantioselective synthesis of chiral 3-hydroxyindolenines, and, the nucleophilic addition of ortho-C-H to carbonyl group might be the determining step of enantioselectivity.In addition, the isolated chiral 3aq (98% ee) was transformed to the final product 4aq with 97% ee after treated with TsOH•H 2 O, which demonstrated that the exclusive 1,2-ester migration occurred after nucleophilic addition of ortho-C-H to carbonyl group.With the diphenyl phosphate as the catalyst, only 47% yield of rac-3aq was obtained as well as ketimine 7 as the by-product.The isolated 7 could be transformed to the 4aq with 98% ee under the standard conditions." In addition, we conducted the DFT calculations (Fig. 5) for this process which supported the above results."As shown in Fig. 5 DFT calculation was further employed to disclose the mechanism for the TsOH-catalyzed intramolecular 1,2-eater migration of 3-hydroxyindolenines 3aq.The binding of TsOH with 3aq through hydrogen bonding produced intermediate Int10.The following hydrogen transfer from TsOH to imine could generate zwitterionic intermediate Int12.Subsequently, the intramolecular 1,2-ester migration proceed via transition state TS13 to afford the product 4aq accompanied by regenerating of TsOH with an exergonic free energy of 9.5 kcal/mol.Optimized geometric for the transition states TS13 showed that the bond length of the forming and breaking C-C bond was 2.01 and 2.01 angstrom, respectively, suggesting that a concerted migration process could occur.Therefore, the chirality information of 3-hydroxyindolenine 3aq could deliver completely to 3oxindoles 4aq, which was well consistent with experimental observations."3) In the SI, P95-96, the HPLC spectra indicated that there are two diastereoisomers for compound 4dq with a dr value of 1:1.Are there two stereogenic centers?This result should be discussed in the manuscript.

Responses:
The compound 4dq contain both a chiral quaternary carbon and an axially chiral center.The discussion was added into the manuscript."Among them, product 4dq with two stereogenic centers of a chiral quaternary carbon and an axially chiral center (1:1 dr)"

To the comments of Reviewer 2
In the manuscript, Cui and co-workers reported the organocatalyzed construction of chiral 3-oxindoles from primary 1-naphthyl-type amine and 2,3-diketoesters, through a sequential enantioselective ortho-FC reaction, condensation and 1,2-ester migration.A series of chiral 3-oxinodles bearing a tetrasubstituted stereogenic center was achieved in good yields and enantioselectivities.It is challenging to realize the intermolecular ortho-FC reaction of primary aryl amines and ketones, due to the side condensation reaction and para-selectivity.Some interesting results were presented in the manuscript, and the direct construction of the related scaffolds, which may have potential applications, is challenging.This reviewer thinks that the current work might contain the novel findings meriting the publication on Nat.Commun., however, a number of issues might be addressed before decision is made, especially for the mechanism study.

Responses:
We thank the Reviewer 2 very much for the support and valuable comments!
We have addressed the issues including detailed mechanism study.1) In general, this manuscript was not well prepared.For example, the data in Table 1 were not clearly elucidated.According the formula in Table 1, two steps were required to give the final product 4aa, but the authors did not mention it in the text.In addition, TsOH was used for some entries, and no explanation was provided too.The authors should check the whole manuscript, guaranteeing it is written in a clearly understandable pattern.

Responses:
The whole manuscript, especially, introduction and investigation of reaction condition were revised.The two steps reaction introduction was added in page 4-5 and entries 5-9 in Table 1.2) The final enantioselective 1,2-ester migration process is intriguing; nevertheless, the suggested direct migration of ester group to electrophilic ketimine group might not be reasonable.Since TsOH was used for the ester migration reaction at rt in one-pot, did the chiral PA also play a role in this process?More control experiments might be conducted with the isolated chiral 3aq (Fig. 2): Will the ee value of chiral 3aq be changed when sole TsOH is used?Moreover, the authors are strongly encouraged to conduct some DFT calculations to illuminate the reaction pathway and the stereocontrol modes.

Responses:
The exclusive enantioselective [1,2]-ester migration was demonstrated by the control experiments in Fig. 2a.The chiral PA could also catalyze the 1,2-ester migration, but it went very slowly under the room temperature.
Hence, TsOH was add to accelerate this process."To validate if the 3hydroxyindolenine 3 was a key intermediate, the control experiment of 1a and 2q using (S)-6b as the catalyst was conducted (Fig. 2a).3aq was obtained in 99% yield with 98% ee.This result implied that this methodology could also be used for catalytic enantioselective synthesis of chiral 3-hydroxyindolenines, and, the nucleophilic addition of ortho-C-H to carbonyl group might be the determining step of enantioselectivity.In addition, the isolated chiral 3aq (98% ee) was transformed to the final product 4aq with 97% ee after treated with TsOH•H 2 O, which demonstrated that the exclusive 1,2-ester migration occurred after nucleophilic addition of ortho-C-H to carbonyl group.With the diphenyl phosphate as the catalyst, only 47% yield of rac-3aq was obtained as well as ketimine 7 as the by-product.The isolated 7 could be transformed to the 4aq with 98% ee under the standard conditions."To shine a light on the origin of the enantioselectivity, we further conducted the non-covalent Interaction (NCI) analysis for the key transition states TS6-RS, TS6-RR, TS6-SR, and TS6-SS.As shown in Fig. 4, the optimal matching factor for transition state TS6-RS not only originated from the π−π interaction (highlighted by blue circles) between the 9-anthryl groups in the arm of CPA catalyst and 1-naphthylamine 1a and 2,3-diketoester 2q, respectively, but also from the π−π interaction between naphthyl moiety of 1a and thiazolyl moiety of 2a.On the contrary, owing to hydrogen bonding interaction between CPA and 1-naphthylamine 1a leading to an outward naphthyl moiety of 1a, which erased the π−π interaction between the 9-anthryl groups of CPA catalyst and 1a.Therefore, a relatively higher activation free energy would be assigned to the transition state TS6-SR.
Similarly, the deficiency of π−π interaction between naphthyl moiety of 1a and thiazolyl moiety of 2a owing to the opposite direction of those two moieties in transition state TS6-RR and TS6-SS, resulting in unfavorable processes.Therefore, DFT calculation depicted that the π−π interaction plays a pivotal role in the enantioselectivity-determining process.3) Will the transformation of imine product 7 be promoted by a chiral PA?
Responses: The isolated imine 7 could also be transformed to the 4aq with 98% ee under the standard conditions (Fig. 2).
4) In general, the scope for both partners were relatively limited.How about 2-naphthylamine or even aniline-type ones?How about secondary amine substrates?Are the alkyl-substituted diketoesters applicable?
Responses: N-alkyl anilines as the substrates of were also examined and added in the manuscript (page 8-9) and Table 3.
5) Significant ee losses were observed in the transformation of 4ag to 8.

Why?
Responses: We conducted the same transformation for N-alkyl-substituted 3-oxindole 4qq (Fig. 7).The ee losses was not observed.Thus, the ee losses might be relevant with the unknown racemization in the reduction of the N-non-protected chiral 3-oxindole.

To the comments of Reviewer 3
This manuscript by Cui and coworkers presents the use of a chiral phosphoric acid as catalyst for the enantioselective synthesis of chiral 3-oxindoles via ortho-Friedel-Crafts addition and novel [1,2]-ester migration.In particular, the [1,2]-ester migration reported in this paper is rarely seen in reactions.However, firstly, the chemistry presented in this communication is far from being very effective in terms of synthetic application.Meanwhile, the reaction time is too long.In terms of substrate, there are only polycyclic compounds, and there is no benzene as a substrate for reaction.On one hand, When the 2,3-diketoesters is a 2-substituted aromatic ring, the enantioselectivity is only 22% e.e.On the other, the total number of substrates was insufficient to support publication in nature communication.
Responses: Gratifyingly, when using (R)-5c as the catalyst, 4:1 ratio of CH 2 Cl 2 and ODCB as the solvent, (S)-4ao was obtained in excellent yield with 86% ee.N-Alkyl anilines were also examined as shown in Table 3 (page 8-9).Thus, more than 55 substrates could be applied to this protocol.
However, no direct synthesis of related compounds was found in this paper, basically all naphthalene indole compounds.

Responses:
The direct synthesis of chiral 3-oxindoles were shown in Table 3 with anilines substrates.
Thirdly, there is insufficient evidence in mechanism research to demonstrate the formation process of chirality.Finally, the further transformation of the product is too simplistic.For all these reasons, I cannot recommend publication of this work in nature communication.

Responses:
The detailed mechanistic investigation and DFT calculations have been conducted.And the results were added in pages 9-15.The more transformations were investigated and the results were added pages 15-17.
Other issues: 1) Why does the reaction catalyzed with CPA could selectively afford the desired product and the reaction catalyzed with diphenyl phosphate give the imine intermediate.

Responses:
Actually, the reversible imine formation was both exist in the reactions with CPA or diphenyl phosphate as catalyst.The isolated imine 7 could also be transformed to the 4aq with 98% ee under the standard conditions (Fig. 2).The imine was isolated with diphenyl phosphate as catalyst because of the slower reaction rate and insufficient conversion.
2) The reaction proceeds two-steps one pot to afford the final products.
Why not stop in the first step to obtain the chiral imine product, which could further reduce to the chiral amine product?In this way, sufficient data could be obtained.

Responses:
The first step product 3aq could also be isolated and identified.
The reduction of 3aq resulted in indole compound.

Other minor issues
The NMR spectrum should correspond to the serial number of each compound.

Responses:
The compounds numbers have been located at the bottom of the spectrum.For instance: For compounds containing fluorine, their carbon spectrum splitting should be amplified.
Responses: For the compounds containing fluorine (2f, 2j, 2n, 4af, 4aj, 4an and 4xq), the carbon spectrum splitting were amplified: We deeply appreciate your reconsideration of our manuscript, and we are looking forward to receiving the comments from the reviewers and yourself.If you have any queries, please don't hesitate to contact us.

Sincerely yours, Xiuling Cui
Reviewer #2: Remarks to the Author: In the revised manuscript, the authors have significantly expanded the substrate scope; in particular, the successful application of N-alkyl anilines to construct the expected products is impressive.Moreover, DFT calculations were conducted to elucidate the whole reaction process, and an unusual 1,2-ester migration is interesting.Considering the progress has been made, this reviewer thinks the current work merits the publication on Nat.Commun.There are many spelling and grammar errors in the text.The authors should carefully polish the manuscript accordingly.For example, in the abstract section, "unprecedent".
Reviewer #3: Remarks to the Author: The authors have addressed all the concerns such as the substrate scopes and the reaction mechanism.Meanwhile, the quality of the manuscript have been improved based on the suggestions of the referees.Therefore,i think it's suitable for nature communications.
Reviewer #4: Remarks to the Author: During the revision of the manuscript, the authors have performed extensive DFT calculations to propose a reaction mechanism and to identify the origin of the enantioselctivity.Certainly, these additional studies would strength the work, but I am not convinced that they would change the overall interest for a broad audience of Nature Communications.This is a specific reaction mechanism that is not related to other organic reactions, nor the explanation of the enantionselectivity from pi-pi interactions, are novel.Besides these considerations, in my opinion, there are also some relevant issues on the discussion of the DFT results that must be considered during revision of the manuscript.
Figure 4 compares different enantiomeric pathways, identifying pi-pi interactions as key factors governing enantioselectivity.These types of non-bonding interactions are not well reproduced by classical DFT functionals, and classical dispersion corrections are normally included in the calculations.
Here, the authors use M06-2X functional without explicit dispersion.Thus, the authors should say a word on the quantitative performance of M06-2X functional for evaluating pi-pi interactions, because they are crucial for understanding enantioselectivity.
The assessment of enantioselectivity is based on the relative free-energies of isomeric transition states TS6.This assumes Curtin-Hammett conditions: rapid pre-equilibria of reactants and irreversible reaction.The energy values of the energy profile in Figure 3 do not indicate an irreversible reaction, because the low energy barriers and similar relative energies of the intermediates.It is true that the reaction could became irreversible from Int9.However, the part of the mechanism connecting the socalled Int9 and Int10 is not characterized.Therefore, the reversibility or irreversibility of the proposed enantioselectivity-determining step cannot be concluded.To sum up, two aspects should be further discussed: a) the irreversibly of the proposed enantioselectivity-determining step, and b) the description of the full mechanism connecting the reactants with the products.
In line 147, the authors state: "to clarify the enantioselectivity ortho addition as the turnover-limiting of this reaction".However, according to current DFT data, the rate-determining process corresponds to the energy difference between TS13 and Int10.
Thank you very much for your positive decision on our manuscript titled "Enantioselective de novo construction of 3-oxindoles via organocatalyzed formal [3+2] annulation from simple arylamines".
According the comments from reviewers, this manuscript was revised.The responses to the comments and the corresponding changes are disclosed as follows: To the comments of Reviewer 2 In the revised manuscript, the authors have significantly expanded the substrate scope; in particular, the successful application of N-alkyl anilines to construct the expected products is impressive.Moreover, DFT calculations were conducted to elucidate the whole reaction process, and an unusual 1,2-ester migration is interesting.Considering the progress has been made, this reviewer thinks the current work merits the publication on Nat.Commun.
There are many spelling and grammar errors in the text.The authors should carefully polish the manuscript accordingly.For example, in the abstract section, "unprecedent".

Responses:
We sincerely appreciate for your kind comments.The manuscript was carefully polished.For instance, in the abstract, "unprecedent" was changed to "unprecedented".In the last line, page 11, "could occur" was changed to "occurs".In page 15, "wavelength" was changed to "wavelengths" and "stokes shift" was changed to "stokes shifts".

To the comments of Reviewer 3
The authors have addressed all the concerns such as the substrate scopes and the reaction mechanism.Meanwhile, the quality of the manuscript have been improved based on the suggestions of the referees.Therefore, i think it's suitable for nature communications.
Responses: Thanks for your kind comments.

To the comments of Reviewer 4
During the revision of the manuscript, the authors have performed extensive DFT calculations to propose a reaction mechanism and to identify the origin of the enantioselectivity.Certainly, these additional studies would strength the work, but I am not convinced that they would change the overall interest for a broad audience of Nature Communications.This is a specific reaction mechanism that is not related to other organic reactions, nor the explanation of the enantioselectivity from pi-pi interactions, are novel.Besides these considerations, in my opinion, there are also some relevant issues on the discussion of the DFT results that must be considered during revision of the manuscript.
Responses: Thanks for your favorable comments on our manuscript.We Responses: According to your suggestion, the sentence "The relative free energy profiles were calculated by M06-2X density functional, which was already parametrized to account for dispersion interaction."was added in page 11.
2) The assessment of enantioselectivity is based on the relative free- Responses: Thanks for your valuable suggestion, which helps us improve the quality of the manuscript.To clarify that the intramolecular nucleophilic C-H addition of 1-naphthylamine 1a at the carbonyl group of 2,3-diketoester via transition state TS6-RS is an irreversible step, the full mechanism was further taken into consideration.The calculated results are as follows and also the figure 3 was revised.The calculated full energy profiles depicted that the activation free energy of nucleophilic addition via TS6-RS is 9.3 kcal/mol, which is higher than that of the subsequent transformations of its generated zwitterionic intermediate Int7-RS.
Therefore, the nucleophilic addition step could be considered an irreversible and rate-determination step for the formation of 3hydroxyindolenine 3aq. 3) In line 147, the authors state: "to clarify the enantioselectivity ortho addition as the turnover-limiting of this reaction".However, according to current DFT data, the rate-determining process corresponds to the energy difference between TS13 and Int10.
Responses: This conclusion "ortho-Friedel-Crafts addition to carbonyl group might be the rate-limiting step for the formation of 3hydroxyindolenine 3aq" was drawn from the Hammett analysis (Figure 2b).Based on this fact, the corresponding description was revised as follows: "The condensations of a series of 2,3-diketoesters with 1-naphthylamine were performed to illustrate the impact of the electronic effect on the step of enantioselective ortho addition (Fig. 2b).A positive value (0.74) was observed based on the Hammett analysis, implying that the reaction rate of the 2,3-diketoester with electron-withdrawing groups at the para position to the central carbonyl was faster than that of electron-donating groups, indicating that the ortho-Friedel-Crafts addition to carbonyl group might be the rate-limiting step for the formation of 3-hydroxyindolenine 3aq." The changes were highlighted by yellow color in revised manuscript and supporting information.Please contact with us freely if there is other information to be addressed.
Reviewer #4: Remarks to the Author: The revision of the manuscript has clarified my main concerns related with DFT calculations.The new energy profile reported in Figure 3 indicates that transition state TS6 corresponds to an irreversible step, and corresponds to the enantioselectivity determining step under Curti-Hammet conditions.The new text clarifies that the discussion of rate-determining process refers to the formation of product 3aq.My only suggestion here refers to Figure 2b, in which the authors could note more clearly that the Hammet plot corresponds to the first of the two consecutive reactions reported.Still, I see that the main interest of the manuscript does not relay in DFT mechanistic characterization, but in the synthetic utility of the reaction that has been positively evaluated by more competent reviewers.Thus, I glad to support the publication of this work in Nat.Commun.Journal.
Thank you very much for your acceptance on our manuscript titled "Enantioselective de novo construction of 3-oxindoles via organocatalyzed formal [3+2] annulation from simple arylamines".
According the comments from reviewer 4, this manuscript was revised.
The responses to the comments and the corresponding changes are disclosed as follows: To the comments of Reviewer 4 Reviewer #4 (Remarks to the Author): Comments：The Commun.Journal.

Responses:
We sincerely thank this reviewer for his/her positive comments on our work.To make it clearer that the Hammett plot corresponds to the first of two consecutive reactions reported, the caption of Figure 2b (Figure 4b in revised manuscript) was revised as "Hammett analysis of the ortho- Friedel-Crafts addition of 1-naphthylamine to 2,3-diketoesters".

Fig. 3 .
Fig. 3. Calculated free energy profiles for the chiral phosphoric acid

Fig. 4 .Fig. 5 .
Fig. 4. Non-covalent Interaction (NCI) analysis for the key transition would like to emphasize that the synthesis of 3-oxindoles bearing chiral at the C2 position are of paramount importance in chemical community, since they are ubiquitous structural motifs that are found in natural products and biologically active compounds and also play a significant role in a variety of synthetic transformations.However, the existing reaction modes in literatures mainly rely on multistep reactions starting from 2-substituted indoles (Ref 10-26), the de novo construction of chiral 3-oxindoles from easily available starting materials as well as simple operation has been highly desired.In this work, the ready availability of arylamines were employed as the starting materials with 2,3-diketoesters via ortho-C-H addition to directly construct 3-hydroxyindolenines with chiral tertiary alcohols.This protocol offers a flexible platform to access a wide array of chiral 3-oxindoles with good yields, excellent functional group tolerance, and enantioselectivity.The rapid assembly of biologically valuable chiral 3-oxindole derivatives (4Jq-4Nq) confirmed the compatibility and practicability of this methodology.Moreover, the π-π interaction between substrates and catalyst, which leads to the observed enantioselectivity, was revealed by detailed mechanistic experiments and DFT calculations, which might provide an avenue not only for the construction of diversity and complexity chiral oxindole derivatives but also for CPA-catalyzed enantioselectivity transformations.In addition, incorporating the reviewer's constructive comments, we have revised the manuscript and the detailed responses are listed as bellows:1) Figure4compares different enantiomeric pathways, identifying pi-pi interactions as key factors governing enantioselectivity.These types of non-bonding interactions are not well reproduced by classical DFT functionals, and classical dispersion corrections are normally included in the calculations.Here, the authors use M06-2X functional without explicit dispersion.Thus, the authors should say a word on the quantitative performance of M06-2X functional for evaluating pi-pi interactions, because they are crucial for understanding enantioselectivity.
energies of isomeric transition states TS6.This assumes Curtin-Hammett conditions: rapid pre-equilibria of reactants and irreversible reaction.The energy values of the energy profile in Figure3do not indicate an irreversible reaction, because the low energy barriers and similar relative energies of the intermediates.It is true that the reaction could became irreversible from Int9.However, the part of the mechanism connecting the so-called Int9 and Int10 is not characterized.Therefore, the reversibility or irreversibility of the proposed enantioselectivity-determining step cannot be concluded.To sum up, two aspects should be further discussed: a) the irreversibly of the proposed enantioselectivity-determining step, and b) the description of the full mechanism connecting the reactants with the products.
revision of the manuscript has clarified my main concerns related with DFT calculations.The new energy profile reported in Figure3indicates that transition state TS6 corresponds to an irreversible step, and corresponds to the enantioselectivity determining step under Curti-Hammet conditions.The new text clarifies that the discussion of ratedetermining process refers to the formation of product 3aq.My only suggestion here refers to Figure2b, in which the authors could note more clearly that the Hammet plot corresponds to the first of the two consecutive reactions reported.Still, I see that the main interest of the manuscript does not relay in DFT mechanistic characterization, but in the synthetic utility of the reaction that has been positively evaluated by more competent reviewers.Thus, I glad to support the publication of this work in Nat.